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FI3609894T3 - Crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid - Google Patents

Crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid Download PDF

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FI3609894T3
FI3609894T3 FIEP18715594.0T FI18715594T FI3609894T3 FI 3609894 T3 FI3609894 T3 FI 3609894T3 FI 18715594 T FI18715594 T FI 18715594T FI 3609894 T3 FI3609894 T3 FI 3609894T3
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methyl
salt
tetrahydrofolic acid
crystalline
sodium
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FIEP18715594.0T
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Finnish (fi)
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Rudolf Moser
Viola Groehn
Fritz Blatter
Martin Szelagiewicz
Stamm Ruth Boehni
Markus Ruettimann
Giuseppe Lapadula
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Merck Patent Gmbh
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
    • C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Claims (24)

PatenttivaatimuksetPatent Claims 1. 5-metyyli-(6S)-tetrahydrofoolihapon kiteinen natriumsuola, jossa 5- metyyli-(6S)-tetrahydrofoolihapon moolisuhde natriumiin on 1:0,5 - 1:1,5, tai sen hydraatit tai solvaatit.1. Crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid, where the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to sodium is 1:0.5 to 1:1.5, or its hydrates or solvates. 2. Patenttivaatimuksen 1 mukainen kiteinen suola, jossa 5-metyyli- (6S)-tetrahydrofoolihapon moolisuhde natriumiin on 1:0,75 - 1:1,25.2. The crystalline salt according to claim 1, wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to sodium is 1:0.75 to 1:1.25. 3. Patenttivaatimuksen 1 tai 2 mukainen kiteinen suola, jossa 5-metyyli- (6S)-tetrahydrofoolihapon moolisuhde natriumiin on 1:1.3. The crystalline salt according to claim 1 or 2, wherein the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid to sodium is 1:1. 4. Ainakin yhden edellisen patenttivaatimuksen mukainen kiteinen suola tunnettu siitä, että suola on 5-metyyli-(6S)-tetrahydrofoolihapon nat- riumsuola ja sillä on PXRD-kuvio, jossa on ainakin yksi tunnusomainen huippu (il- maistuna 20 + 0,29 20 (CuKa-säteily)) kohdassa 6,5, 10,2, 13,1, 15,3, 17,9, 20,5 ja 22,0.4. A crystalline salt according to at least one of the preceding claims characterized in that the salt is the sodium salt of 5-methyl-(6S)-tetrahydrofolic acid and has a PXRD pattern with at least one characteristic peak (expressed as 20 + 0.29 20 (CuKa radiation)) at 6.5, 10.2, 13.1, 15.3, 17.9, 20.5 and 22.0. 5. Ainakin yhden edellisen patenttivaatimuksen mukainen kiteinen suola, tunnettu siitä, että suola on 5-metyyli-(6S)-tetrahydrofoolihapon nat- riumsuola ja sillä on PXRD-kuvio, jossa on ainakin yksi tunnusomainen huippu (il- maistuna 20 + 0,2* 20 (CuKa-säteily)) kohdassa 6,5, 10,2, 12,5, 13,1, 14,8, 15,1, 15,3, 16,1, 17,2, 17,9, 20,4, 20,5, 21,2, 22,0, 22,5 ja 27,2.5. A crystalline salt according to at least one of the preceding claims, characterized in that the salt is the sodium salt of 5-methyl-(6S)-tetrahydrofolic acid and has a PXRD pattern with at least one characteristic peak (expressed as 20 + 0.2 * 20 (CuKa radiation)) in 6.5, 10.2, 12.5, 13.1, 14.8, 15.1, 15.3, 16.1, 17.2, 17.9, 20 .4, 20.5, 21.2, 22.0, 22.5 and 27.2. 6. Ainakin yhden edellisen patenttivaatimuksen mukainen kiteinen suola tunnettu siitä, että 5-metyyli-(6S)-tetrahydrofoolihapon natriumsuo- lalla on kuviossa 1 esitetyn kaltainen PXRD-kuvio.6. A crystalline salt according to at least one of the preceding claims, characterized in that the sodium salt of 5-methyl-(6S)-tetrahydrofolic acid has a PXRD pattern similar to that shown in Figure 1. 7. Ainakin yhden edellisen patenttivaatimuksen mukainen kiteinen suola, tunnettu siitä, että 5-metyyli-(6S)-tetrahydrofoolihapon natriumsuola on 5-metyyli-(6S)-tetrahydrofoolihapon mononatriumsuola.7. A crystalline salt according to at least one of the preceding claims, characterized in that the sodium salt of 5-methyl-(6S)-tetrahydrofolic acid is the monosodium salt of 5-methyl-(6S)-tetrahydrofolic acid. 8. Ainakin yhden edellisen patenttivaatimuksen mukainen kiteinen suola, jolla on ainakin 99 %:n tai korkeampi kemiallinen puhtaus.8. A crystalline salt according to at least one of the preceding claims, having a chemical purity of at least 99% or higher. 9. Prosessi ainakin yhden patenttivaatimuksen 1-7 mukaisen 5-me- tyyli-(6S)-tetrahydrofoolihapon kiteisen natriumsuolan aikaansaamiseksi, käsit- täen vaiheet: a) asetetaan käytettäväksi 5-metyyli-(6S)-tetrahydrofoolihappoa, va- linnaisesti soveltuvassa liuottimessa tai liuottimien seoksessa; b) lisätään natriumhydroksidia vaiheen a) koostumukseen; c) lisätään ko-suolanmuodostaja ja valinnaisesti liuotin tai liuottimien seos vaiheen b) koostumukseen, tai lisätään vaiheen b) koostumus ko-suolanmuo- dostajaan ja liuottimeen tai liuottimien seokseen; d) kiteytys;9. A process for obtaining the crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid according to at least one of claims 1-7, comprising the steps: a) 5-methyl-(6S)-tetrahydrofolic acid is used, optionally in a suitable solvent or in a mixture of solvents; b) adding sodium hydroxide to the composition of step a); c) adding a co-salt former and optionally a solvent or a mixture of solvents to the composition of step b), or adding the composition of step b) to a co-salt former and a solvent or a mixture of solvents; d) crystallization; e) valinnaisesti lisätään enemmän liuotinta tai liuottimien seosta; ja f) eristetään aikaansaatu kiintoaine.e) optionally adding more solvent or a mixture of solvents; and f) isolating the resulting solid. 10. Patenttivaatimuksen 9 mukainen prosessi, tunnettu siitä, että 5-metyyli-(6S)-tetrahydrofoolihapon ja natriumhydroksidin moolisuhde vai- heessab) on alueella 1:0,5 - 1:1,5.10. The process according to claim 9, characterized in that the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid and sodium hydroxide in step b) is in the range 1:0.5 to 1:1.5. 11. Patenttivaatimuksen 9 tai 10 mukainen prosessi, tunnettu siitä, että 5-metyyli-(6S)-tetrahydrofoolihapon ja ko-suolanmuodostajan moolisuhde vaiheessa c) on alueella 1:0,5 - 1:3.11. The process according to claim 9 or 10, characterized in that the molar ratio of 5-methyl-(6S)-tetrahydrofolic acid and co-salt former in step c) is in the range 1:0.5 to 1:3. 12. Ainakin yhden patenttivaatimuksen 9-11 mukainen prosessi, tunnettu siitä, että vaiheen a), c) ja/tai e) mukainen liuotin ja/tai liuottimien seos valitaan ryhmästä, joka koostuu vedestä, vesiliukoisista alkoholeista, metano- lista, etanolista, isopropanolista, n-propanolista, asetonitriilistä, tetrahydrofuraa- nista, asetonista, metyylietyyliketonista, metyyli-isobutyyliketonista, bentsyylial- koholista ja niiden seoksista.12. The process according to at least one of claims 9-11, characterized in that the solvent and/or mixture of solvents according to step a), c) and/or e) is selected from the group consisting of water, water-soluble alcohols, methanol, ethanol, isopropanol , n-propanol, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, benzyl alcohol and their mixtures. 13. Ainakin yhden patenttivaatimuksen 9-12 mukainen prosessi, tunnettu siitä, että vaiheen c) ko-suolanmuodostaja on orgaaninen emäs, jonka pKa-arvo on 6-11.13. The process according to at least one of claims 9-12, characterized in that the co-salt former of step c) is an organic base with a pKa value of 6-11. 14. Ainakin yhden patenttivaatimuksen 9-13 mukainen prosessi, tunnettu siitä, että vaiheen c) ko-suolanmuodostaja on orgaaninen emäs, jonka pKa-arvoon 7-10.14. The process according to at least one of claims 9-13, characterized in that the co-salt former of step c) is an organic base with a pKa value of 7-10. 15. Ainakin yhden patenttivaatimuksen 9-14 mukainen prosessi, tunnettu siitä, että vaiheen c) ko-suolanmuodostaja valitaan ryhmästä, joka koostuu 4-(2-hydroksietyyli)-morfoliinista, 1-(2-hydroksietyyli)-pyrrolidonista, imidatsolista, 2-dimetyyliaminoetanolista ja tert-butyyliamiinista; ja niiden seok- sista.15. The process according to at least one of claims 9-14, characterized in that the co-salt former of step c) is selected from the group consisting of 4-(2-hydroxyethyl)-morpholine, 1-(2-hydroxyethyl)-pyrrolidone, imidazole, 2- from dimethylaminoethanol and tert-butylamine; and their mixtures. 16. Ainakin yhden patenttivaatimuksen 15 mukainen prosessi, tu n - nettu siitä, että vaiheen c) ko-suolanmuodostaja on 4-(2-hydroksietyyli)-morfo- liini.16. The process according to at least one of claims 15, characterized in that the co-salt former of step c) is 4-(2-hydroxyethyl)-morpholine. 17. Ainakin yhden patenttivaatimuksen 9-16 mukainen prosessi, tunnettu siitä, että vaiheessa d) lämpötila on vähintään 30 °C.17. The process according to at least one of claims 9-16, characterized in that in step d) the temperature is at least 30 °C. 18. Ainakin yhden patenttivaatimuksen 9-17 mukainen prosessi, tunnettu siitä, että vaiheessa a), b), c) ja/tai d) lisätään siemenkiteitä.18. The process according to at least one of claims 9-17, characterized in that in step a), b), c) and/or d) seed crystals are added. 19. Farmaseuttinen koostumus, elintarvikelisäaine tai vitamiinival- miste, joka käsittää ainakin yhden patenttivaatimuksen 1-7 mukaisen 5-metyyli- (6S)-tetrahydrofoolihapon kiteisen natriumsuolan ja valinnaisesti yhden tai use- amman hyväksyttävän apuaineen.19. Pharmaceutical composition, food additive or vitamin preparation, comprising at least one crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid according to claims 1-7 and optionally one or more Amma-acceptable excipients. 20. Patenttivaatimuksen 19 mukainen farmaseuttinen koostumus tab- lettien, kapselien, oraalisten nestemäisten preparaattien, jauheiden, lyofilisaattien, rakeiden, imeskelytablettien, rekonstituoitavien jauheiden, injektoitavien tai in- fusoitavien liuosten tai suspensioiden tai lääkepuikkojen muodossa.20. Pharmaceutical composition according to claim 19 in the form of tablets, capsules, oral liquid preparations, powders, lyophilisates, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions, or medicinal sticks. 21. Patenttivaatimuksen 19 tai 20 mukainen farmaseuttinen koostu- mus, joka käsittää edelleen ainakin yhden terapeuttisen lisäaineen.21. The pharmaceutical composition according to claim 19 or 20, which further comprises at least one therapeutic additive. 22. Patenttivaatimusten 19-21 mukainen farmaseuttinen koostumus, joka on farmaseuttinen koostumus käytettäväksi annettavaksi oraalisesti, parente- raalisesti, intramuskulaarisesti, intraspinaalisesti, intratekaalisesti, peridontaali- — sesti, topikaalisesti tai rektaalisesti.22. A pharmaceutical composition according to claims 19-21, which is a pharmaceutical composition for use orally, parenterally, intramuscularly, intraspinally, intrathecally, peridontally, topically or rectally. 23. Ainakin yhden patenttivaatimuksen 1-7 mukaisen 5-metyyli-(6S)- tetrahydrofoolihapon kiteisen natriumsuolan käyttö ainesosana lääkkeiden ja/tai elintarvikelisäaineiden tuotantoon.23. Use of the crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid according to at least one of claims 1-7 as an ingredient for the production of medicines and/or food additives. 24. Ainakin yhden patenttivaatimuksen 1-7 mukainen 5-metyyli-(6$)- —tetrahydrofoolihapon kiteinen natriumsuola käytettäväksi homokysteiinin alenta- miseen, anemian, hermostoputken sulkeutumishäiriöiden, sydän- ja verisuonisai- rauksien, masennuksen, kognitiivisten taitojen häiriöiden, Alzheimerin taudin ja osteoporoosien hoidossa ja/tai käytettäväksi alhaisen plasman ja/tai alhaisen pu- naisten verisolujen folaatin ja/tai alhaisen selkäydinnesteen folaatin ja/tai alhai- sen ääreis- tai keskushermoston folaatin dietaarisessa hallinnassa.24. The crystalline sodium salt of 5-methyl-(6$)-tetrahydrofolic acid according to at least one of claims 1-7 for use in lowering homocysteine, anemia, neural tube closure disorders, cardiovascular diseases, depression, cognitive skills disorders, Alzheimer's disease and osteoporosis in the treatment and/or for use in the dietary management of low plasma and/or low red blood cell folate and/or low cerebrospinal fluid folate and/or low peripheral or central nervous system folate.
FIEP18715594.0T 2017-03-31 2018-03-28 Crystalline sodium salt of 5-methyl-(6S)-tetrahydrofolic acid FI3609894T3 (en)

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US20160207925A1 (en) * 2013-12-31 2016-07-21 Gianni Fracchia L-methylfolate salt preparations, medicaments, and nutritional supplements comprising such salts thereof
WO2015193778A1 (en) * 2014-06-16 2015-12-23 Mylan Laboratories Ltd. Crystalline form of levomefolate calcium

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WO2018178141A1 (en) 2018-10-04
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RU2019133594A3 (en) 2021-07-21
JP7285785B2 (en) 2023-06-02
RU2019133594A (en) 2021-04-30
AU2018246265B2 (en) 2022-07-07
US11185545B2 (en) 2021-11-30
CA3058287A1 (en) 2018-10-04
DK3609894T3 (en) 2024-09-09
ES2989869T3 (en) 2024-11-28
CN110475778A (en) 2019-11-19
KR20190136029A (en) 2019-12-09
US20220016121A1 (en) 2022-01-20
EP3609894B1 (en) 2024-07-17
PT3609894T (en) 2024-08-29
US20200030333A1 (en) 2020-01-30
HUE068578T2 (en) 2025-01-28
AU2018246265A1 (en) 2019-11-14

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